Research Objective: Cardiovascular Aging Advancing age is accompanied by an increased prevalence of cardiovascular disease, including atherosclerosis, myocardial infarction, and stroke. Underlying all of these conditions lies the aging blood vessel, damaged with a dysfunctional endothelium. Evidence has secured aging as a strong predictor of endothelial dysfunction, yet potential therapies are unknown. Consumption of flavonoid-rich beverages, including tea and red wine, is associated with a reduction in coronary events. Cocoa can contain extraordinary concentrations of flavonoids, shown to activate nitric oxide synthase (NOS) in vitro. We have demonstrated that cocoa rich in these flavonoids induced peripheral vasodilation, improving endothelial function in healthy people. Furthermore, through infusion of the specific NOS inhibitor L-NAME, we have demonstrated that the mechanism is nitric-oxide dependent. We propose that responsiveness to these flavonoids, namely via activation of NOS, is age-dependent, increasing with advancing age. Specifically, we plan to extend preliminary observations that the beneficial effects of flavonoid-rich cocoa on augmenting endothelial function are greater in the elderly than in the young. Pulse wave amplitude will be measured in the finger in response to flavanol-rich cocoa, with flavanol-poor cocoa as a control. To test the hypothesis that these actions are dependent upon NO synthesis, we will measure responsiveness to the naturally occurring substrate L-arginine before and after one week of flavanol-rich cocoa in elderly subjects. We anticipate that the vasodilator effects of arginine will be enhanced after flavanol-rich cocoa, and that L-NAME will inhibit the response. With this proposal Dr. Fisher will enter a new area of clinical research in cardiovascular aging, with investigations into improvement of endothelial function that are novel, intriguing and broadly applicable. She will be solely responsible for planning, directing and executing the proposed two-year project on the GCRC of the Brigham and Women's Hospital. She will be well-positioned to submit an application for an RO1 with results from this study. Therapeutic interventions aimed at restoring vascular endothelial function hold tremendous clinical promise.